EMA EFPIA workshop Break-out session no.3 Case Study Title: M&S - - PowerPoint PPT Presentation

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EMA EFPIA workshop Break-out session no.3 Case Study Title: M&S - - PowerPoint PPT Presentation

Nov 24, 2023 277 likes •453 views

EMA EFPIA workshop Break-out session no.3 Case Study Title: M&S support to the bridging of a drug with Ethnic PK-differences Disclaimer The view and opinions expressed in these slides are my own and do not necessarily represent the views

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SLIDE 1

EMA EFPIA workshop

Case Study Title: M&S support to the bridging of a drug with Ethnic PK-differences

Break-out session no.3

Disclaimer The view and opinions expressed in these slides are my own and do not necessarily represent the views of AstraZeneca

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SLIDE 2

Background, Scope

  • First in class for treatment of neuropathic pain
  • How can a clinical development plan (CDP),

aiming to bridge from Western to Japanese, be designed

  • Assumptions, sensitivity to assumptions
  • Results from Phase I modeling
  • Modeling to support program design
  • Considerations

Matts Kågedal 29-30 November 2011 2

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SLIDE 3

Assumption Framework

Disease (Progression) / Safety Disease (Progression) / Safety ADME ADME

Bridge to new population Bridge to new population Bridge to new population Bridge to new population Bridge to new population Bridge to new population

Matts Kågedal 29-30 November 2011 3

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SLIDE 4

ADME ADME

Assumption Framework

Bridge to new population Bridge to new population

Sensitivity to ethnic factors:

PK: Elimination via Metabolism (Enzyme uncertain). Do PK in Japan early

Matts Kågedal 29-30 November 2011 4

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SLIDE 5

Disease (Progression) / Safety Disease (Progression) / Safety

Assumption Framework

Bridge to new population Bridge to new population Bridge to new population Bridge to new population

Sensitivity to ethnic factors:

(Intrinsic and extrinsic) Biomarkers:

  • No biomarkers available.

Efficacy/safety:

  • First in class!
  • Therapeutic index likely to be

narrow Dose response data for Efficacy and safety needed in Japan to bridge results from the West.

Matts Kågedal 29-30 November 2011 5

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SLIDE 6

Japanese vs Caucasian AUC based

  • n last dose data in MAD and J-MAD
  • Higher AUC in Japanese as

compared to Caucasian.

  • Not explained by body

weight

  • No ethnic difference in

protein binding.

Japanese model prediction Caucasian model prediction

Observed and model predicted AUC/dose for Japanese and Caucasian subjects.

  • Additional studies may be

needed to understand mechanism behind PK-difference to improve predictions.

Matts Kågedal 29-30 November 2011

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SLIDE 7

Cmax vs probability of AE

0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 500 1000 1500 2000 2500 3000 3500 S imulated prop Prob for typical indiv Obs Prop J ap Obs Prop C au 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 500 1000 1500 2000 2500 3000 3500 S imulated prop Prob for typical indiv Obs Prop J ap Obs Prop C au 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 500 1000 1500 2000 2500 3000 3500

Day 1 Day 6 Day 12 Japanese West

  • Similar PK-safety relationship for West and Japan, but

limited data (MAD in western and Japanese subjects)

  • Tolerance development to side effect indicated.

Cmax

Proportion with AE

Model is based on logistic regression with tolerance development. Figure showing proportion of subjects with AE in each dose-grope versus the mean Cmax in that group and the model predicted proportion based on simulation.

Model predicted proportion Probability of typical individual

Matts Kågedal 29-30 November 2011 7

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SLIDE 8

Phase II and III program options

(How M&S is used to inform Drug Development) Development options for Japanese population

Assumptions Assumptions

Matts Kågedal 29-30 November 2011 8

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SLIDE 9

Empirical support for assumptions in transition between phases

West Phase IIa West Phase IIa Japan + West Phase IIb Japan + West Phase IIb Japan+West Phase III One dose Japan+West Phase III One dose Regulatory File Regulatory File

Data to support assumptions in the transition between phases

Important Assumptions IIa -> IIb IIb -> III III->File CLJAP <CLW SAD, MAD SAD, MAD, IIb SAD, MAD, IIb, III Similar PK-safety SAD+MAD (limited data) SAD, MAD, IIb SAD, MAD, IIb, III Similar PK-Efficacy None IIb IIb, III Program 2 -Small strata of Japanese in global trials

Matts Kågedal 29-30 November 2011 9

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SLIDE 10

Model based assessment of program

Evaluation conditions (what if):

  • 1. Similar exposure response in Caucasian and Japanese
  • 2. Higher potency in Japanese ( e.g. half exposure -> same

effect) Model:

  • 1. PK based on SAD + MAD
  • 2. Placebo model built based on data from previous trials (in-

house and literature).

  • 3. Assumed exposure response model based on literature,

preclinical data and target product profile Decision criteria for phase III:

  • 1. Is there an ethnic difference in exposure response

Criteria to judge adequacy of program:

  • 1. Precision and bias in estimation of optimal dose for

Japanese and Caucasians

  • 2. Power to detect an ethnic difference in exposure response

for Efficacy and Safety

Matts Kågedal 29-30 November 2011 10

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SLIDE 11

Simulation of program 2 assuming higher potency in Japanese

Example with 1000 simulated programs *

Simul. Ph IIb Simul. Ph IIb Estim. Ph IIb Estim. Ph IIb Simul Ph III Same exposure J(20%)+W Simul Ph III Same exposure J(20%)+W Ethnic difference? No Yes Simul Ph III Larger Jap group Dose can differ J(40%)+W Simul Ph III Larger Jap group Dose can differ J(40%)+W Estim. (IIb+III) Estim. (IIb+III) Ethnic diff? No Yes Same dose Same dose Estim. (IIb+III) Estim. (IIb+III) Ethnic diff? No Yes Same dose Same dose Different dose Different dose Different dose Different dose

N=1000 N=285 N=35 N=715 N=250 N=15 N=700

Ethnic difference detected in 95% of simulated programs

* Made up example for

  • illustration. No simulations

were actually performed.

Matts Kågedal 29-30 November 2011 11

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SLIDE 12

Precision of estimated dose - program 2

(example for illustration)

Optimal dose Density

Two fold difference in potency:

Result: Power=95% Optimal dose Density

No difference in potency:

5% of studies with detected difference True Est

  • Repeat for program 1 and 3 and compare outcome, cost and time
  • Different endpoints can be evaluated. E.g. precision of minimum

effective dose.

Japan West

Matts Kågedal 29-30 November 2011 12

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SLIDE 13

Important considerations Important considerations

  • The required precision in the ethnic comparison needs

consideration

  • All ethnic groups are important.
  • Modeling can allow estimation of the individual

components of intrinsic/extrinsic factors, using the data more effectively

  • Not all groups will have empirical support. Models built
  • n biological principles can improve predictions. (Eg

data on Koreans in Korea and the west can support prediction of response in Japanese in the West)

  • Acceptance to base dose selection on target exposure is

needed (Phase III dose may not have been studied in

  • ne or both populations)

Matts Kågedal 29-30 November 2011 13

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SLIDE 14

Backups

Matts Kågedal 29-30 November 2011 14

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SLIDE 15

Precision of estimated dose CDP 3

(example for illustration)

Optimal dose Density

Two fold difference in potency:

Optimal dose Density

No difference in potency:

True Est Program is more costly and require more patients. Better precision if there is a 2-fold difference and worse if there is no difference.

(Grey curves= precision based on program 2.)

Japan West

Matts Kågedal 29-30 November 2011 15

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SLIDE 16

Similarity West-Japan

Uncertainty Severity/importance of consequence

PK, Efficac y, Safety

mitigate

Development goal

Evidence build

Matts Kågedal 29-30 November 2011 16